HLA-DRA variants predict penicillin allergy in genome-wide fine-mapping genotyping

Background: Immediate reactions to b-lactams are the most common causes of anaphylactic reactions and can be life-threatening. The few known genetic factors influencing these reactions suggest a link with atopy and inflammation. Objective: We performed a fine-mapping genome-wide association study of the genetic predictors of b-lactam allergy to better understand the underlying mechanisms. Methods: We studied 387 patients with immediate allergic reactions to b-lactams and 1124 paired control subjects from Spain. We replicated the results in 299 patients and 362 paired control subjects from Italy. Results: We found significant associations with the single nucleotide polymorphisms rs4958427 of ZNF300 (c. 64-471G> A, P 5 9.9 3 10 29), rs17612 of C5 (c. 4311A> C [p. Glu1437Asp], P 5 7.5 3 10 27), rs7754768 and rs9268832 of the HLA-DRA j HLA-DRB5 interregion (P 5 1.6 3 10 26 and 4.9 3 10 26), and rs7192 of HLA-DRA (c. 724T> G [p. Leu242Val], P 5 7.4 3 10 26) in an allelic model, with similar results in an additive model. Single nucleotide polymorphisms of HLA-DRA and ZNF300 predicted skin test positivity to amoxicillin and other penicillins but not to cephalosporins. A haplotype block in HLA-DRA and the HLA-DRA j HLA-DRB5 interregion encompassed a motif involved in balanced expression of the a-and b-chains of MHC class II, whereas rs7192 was predicted to influence a-chain conformation. HLA-DRA rs7192 and rs8084 were significantly associated with allergy to penicillins and amoxicillin (P 5 6.0 3 10 24 and P 5 4.0 3 10 24, respectively) but not to cephalosporins in the replication study. Conclusions: Gene variants of HLA-DRA and the HLA-DRA j HLA-DRB5 interregion were significant predictors of allergy to penicillins but not to cephalosporins. These data suggest complex gene-environment interactions in which genetic susceptibility of HLA type 2 antigen presentation